1. Field of the Invention
This invention relates to a process for producing an addition compound of a dipeptide ester and an amino acid ester and more particularly to a process for producing an addition compound of N-benzyloxycarbonyl-.alpha.-L-aspartyl-L-phenylalanine methyl ester and phenylalanine methyl ester from aspartic acid, benzyloxycarbonyl chloride, phenylalanine and methanol, in which an enzymatic reaction is utilized.
2. Description of the Prior Art
It has been known that an addition compound of a dipeptide ester and an amino acid ester is produced by reacting a monoaminodicarboxylic acid, of which amino group is protected, and a monoaminomonocarboxylic acid converted into an ester by protecting its carboxyl group with an lower alkoxyl group, in the presence of a proteotylic enzyme, and further by forming an addition compound of the reaction product and the ester (U.S. Pat. No. 4,165,311).
Thus produced addition compounds are imported materials as intermediates for foods, medicines, pharmaceuticals and the like. Among them, the addition compound of N-benzyloxycarbonyl-.alpha.-L-aspartyl-L-phenylalanine methyl ester and phenylalanine methyl ester (hereinafter referred to as ZAPM.PM for the abbreviation) is particularly important because it can be easily derived to a low calorie sweetener, "aspartame".
According to the above-stated known process, ZAPM.PM is produced any way from N-benzyloxycarbonylaspartic acid (hereinafter referred to as ZA) or its salt and phenylalanine methyl ester (hereinafter referred to as PM) as starting materials. In such a case, isolated (crystallized) ones of these starting materials which are in highly purified state are used.
It is possible in a reaction using an enzyme to cause the inhibition or deactivation of the enzyme depending on the situation when there are impurities in the reaction system and therefore it is general to carry out the reaction in avoiding their coexistence.
Crystalline ZA is usually obtained in a way in that after aspartic acid and benzyloxycarbonyl chloride are reacted in an aqueous solution in the presence of a base, ZA is crystallized by adding an acid to convert pH of the reaction solution into the acidic side, isolating and drying it. The other starting material, PM (hydrochloric acid salt) is obtained in that after phenylalanine is reacted with methanol in the presence of hydrogen chloride, methanol is removed by distillation to isolate crystalls of hydrochloric acid salt of PM which is then dried.